I. Field of the Invention
The present invention provides triterpenoid derivatives, as well as processes for the preparation of such derivatives. The invention also provides methods for prevention and/or treatment of cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotropic lateral sclerosis, rheumatoid arthritis, inflammatory bowel disease, and all other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide (NO) or prostaglandins.
II. Description of Related Art
One of the major needs in cancer prevention is the development of effective and safe new agents for chemoprevention. In particular, there is a need for chemopreventative agents targeted at mechanisms known to be involved in the process of carcinogenesis. In recent years, there has been a resurgence of interest in the study of mechanisms of inflammation that relate to carcinogenesis and in the use of such mechanisms as the basis for development of new chemopreventative agents.
The concept that inflammation and carcinogenesis are related phenomena has been the subject of many studies that have attempted to link these two processes in a mechanistic fashion (Sporn and Roberts, 1986; Ohshima and Bartsch, 1994). The enzymes that mediate the constitutive synthesis of NO and prostaglandins from arginine and arachidonate, respectively, have relative little significance for either inflammation or carcinogenesis. In contrast, inducible nitric oxide synthase (iNOS) and inducible cycloxygenase (COX-2) both have critical roles in the response of tissues to injury or infectious agents (Moncada et al., 1991; Nathan and Xie, 1994; Siebert and Masferrer, 1994; Tamir and Tannebaum, 1996). These inducible enzymes are essential components of the inflammatory process, the ultimate repair of injury, and carcinogenesis. While physiological activity of iNOS and COX-2 may provide a definite benefit to the organism, aberrant or excessive expression of either iNOS or COX-2 has been implicated in the pathogenesis of many disease processes, particularly in chronic degeneration of the central nervous system, carcinogenesis, septic shock, cardiomyopathy, and rheumatoid arthritis.
Triterpenoids, biosynthesized in plants by the cyclization of squalene, are used for medicinal purposes in many Asian countries; and some, like ursolic and oleanolic acids, are known to be anti-inflammatory and anti-carcinogenic (Huang et al., 1994; Nishino et al., 1988). However, the biological activity of these naturally occurring molecules is relatively weak, and therefore the synthesis of new analogs to enhance their potency was undertaken (Honda et al., 1997; Honda et al., 1998). It was previously reported that several such synthetic analogs can suppress the de novo formation of iNOS and COX-2 in macrophages that have been stimulated by IFN-γ or LPS (Suh et al., 1998). The role of both iNOS and COX-2 as enhancers of carcinogenesis in many organs is receiving increasing attention (Ohshima et al., 1994; Tamir et al., 1996; Takahashi et al., 1997; Ambs et al., 1998; Tsujii et al., 1998; Oshima et al., 1996); suppression of either the synthesis or the activity of these enzymes is therefore a target for chemoprevention (Kawamori et al., 1998). Agents which induce differentiation or suppress proliferation of premalignant or malignant cells represent yet another mechanistic approach to chemoprevention, as well as to chemotherapy, of cancer.
The present inventors have previously reported that 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) (Table 1), its methyl ester and methyl 2-carboxy-3,12-dioxooleana-1,9(11)-dien-28-oate show high inhibitor activity against production of nitric oxide (NO) induced by interferon-γ in mouse macrophages (IC50=0.1 nM level) (Honda et al., 1998; Honda et al., 1999; Honda et al., 2000a; Honda et al., 2000b). The inventors also reported that CDDO is a potent, multifunctional agent in various in vitro assays (Suh et al., 1999). For example, CDDO induces monocytic differentiation of human myeloid leukemia cells and adipogenic differentiation of mouse 3T3-L1 fibroblasts. CDDO also inhibits proliferation of many human tumor cell lines, and blocks de novo synthesis of inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse macrophases. The above potencies have been found at concentrations ranging from 10−6 to 10−9 M in cell culture. Mechanism studies revealed that CDDO is a ligand for peroxisome proliferator-activated receptor γ (PPARγ) (Wang et al., 2000) and induces apoptosis in human myeloid leukemia cells.
However, it would be advantageous to develop compounds exhibiting higher inhibitory activity against the production of nitric oxide induced by interferon-γ in mouse macrophages. The availability of compounds having potency higher than that of CDDO is important for the prevention or treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, and multiple sclerosis.